For small biopharmaceutical companies, the mechanism of action approach may build the most attractive pipeline.
 Dr. Neil Kurtz joined TorreyPines Therapeutics in 2002. He co-founded the contract research organization Worldwide Clinical Trials and has held senior positions with Boot Pharmaceuticals, Bayer, Bristol-Myers Squibb and Merck. |
CEOs of small biopharmaceutical companies will probably agree that their companies have a greater chance of success if they employ a “multiple shots on goal” strategy. A typical approach is for a company to focus on developing multiple product candidates for closely-related indications—cancer, for example. An alternative approach involves constructing a pipeline based on versatile compounds that can be developed for a wide range of indications. In following the second approach, CEOs should consider focusing on a particular mechanism of action.
The development of versatile products has already produced significant results for Big Pharma. Take aspirin, for example. Originally developed to reduce fever, aspirin is now used on a regular basis to alleviate pain, prevent thrombosis, and, as recent data suggest, decrease the incidence of certain cancers of the GI tract. Another example is the selective serotonin reuptake inhibitors (SSRIs). SSRIs were first approved for depression, followed by anxiety disorders and then obsessive-compulsive disorders. Compounds such as Prozac and Zoloft became multi-billion-dollar drugs because of their versatility in treating multiple conditions. In each of the above cases, the multiplicity of use is explained by one common thread: the mechanism of action by which the drugs work.
TorreyPines Therapeutics, La Jolla, Calif., is using the mechanism of action approach to construct its pipeline. In 2003, the company in-licensed a compound called tezampanel from Eli Lilly & Co. Equipped with preclinical and clinical data for the compound and its unique mechanism of action—competitive inhibition of glutamate binding at both the α-amino-3-hydroxy-5methyl-4-isoxazole-proprionic acid (AMPA) and kainate receptor sites—TorreyPines has established tezampanel as the anchor for a broadening of the company’s pipeline.
Glutamate, a common neurotransmitter in the brain, is the most abundant excitatory amino acid in the central nervous system. Receptors for glutamate are also present outside the central nervous system—located on bones, heart, kidneys, pancreas, and even on platelets in the blood.
There has recently been great interest in the role of glutamate and other excitatory amino acids in regulating physiological processes. Glutamate in general, and specifically AMPA/kainate receptor blockade, is now being considered a promising target for treating multiple diseases and disorders and not just those of the central nervous system. It is well known that excess glutamate production, through injury or disease, can have a range of pathological effects. For example, glutamate release increases platelet activation during the generation of a thrombus. Platelets are key players in normal thrombosis formation, and increased platelet aggregation has been implicated in the cause of cardiovascular diseases such as stroke and myocardial infarction.1
Within the central nervous system, increased levels of glutamate can be measured in patients at the onset of a migraine attack. This increase in glutamate activates AMPA and kainate receptors, resulting in the transmission of pain. Tezampanel effectively blocks glutamate from binding to these receptors, thereby relieving the migraine pain.2, 3 In a clinical study, more than two-thirds of patients receiving tezampanel by subcutaneous injection experienced significant relief of headache pain after two hours, going from “severe-or-moderate” to “mild-or-no” pain. This relief was long-lasting with greater than 80% of patients reporting no recurrence of pain or not requiring rescue therapy over 24 hours.
Based solely on its mechanism of action, tezampanel could be effective across a variety conditions that are characterized by excess glutamate production. TorreyPines is also developing an oral version of tezampanel called NGX426. Currently in Phase 1, NGX426 has been shown to be safe and well-tolerated. Initiation of a Phase 1, double-blind, placebo-controlled trial of NGX426 in a capsaicin model for neuropathic pain is planned for the first half of this year. The purpose of this trial is to show that tezampanel is an effective analgesic when administered orally as NGX426.
References
1. Morrell, C.N., Sun, H., Ikeda, M., Beique, J.C., Swaim, A.M., Mason, E., Martin, T.V., Thompson, L.E., Gozen, O., Ampagoomian, D., Sprengel, R., Rothstein, J., Faraday, N., Huganir, R., and Lowenstein, C.J. Glutamate mediates platelet activation through the AMPA receptor. The Journal of Experimental Medicine. Vol. 205, No. 3, 575-584.
2. Vikelis, M. and Mitsikostas, D.M. The role of glutamate and its receptors in migraine. CNS & Neurological Disorders – Drug Targets. Vol. 6, No. 4, 251-257.
3. Sang CN, Ramadan NM, Wallihan RG, Chappell AS, Frietag FG, Smith TR, Silberstein SD, Johnson KW, Phebus LA, Bleakman D, Ornstein PL, Arnold B, Tepper SJ, Vandenhende F. LY293558, a novel AMPA/GluR5 antagonist, is efficacious and well-tolerated in acute migraine. Cephalalgia. 2004, 24, 596-602.
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Tezampanel, the first AMPA/kainate receptor antagonist studied in humans, provides development opportunities across a range of indications from migraine and other chronic pain conditions to epilepsy, muscle spasticity and rigidity and thrombosis. A Phase 2 trial of tezampanel in patients for the treatment of muscle spasticity and rigidity secondary to spinal cord trauma is planned for the second half of 2008.
As the TorreyPines example illustrates, the mechanism of action approach provides a strong platform for developing a commercially attractive pipeline of a small number of product candidates that can have a variety of therapeutic uses—something CEOs of small biopharmaceutical companies should consider.
Tips to approach pipeline construction:
• Pursue mechanism, not indication
• Understand the mechanism’s pros and cons
• Determine whether the hurdles can be realistically addressed and managed
• The extent to which one can predict, understand and work through the challenges will increase the likelihood of success
About the Author
Dr. Neil Kurtz joined TorreyPines Therapeutics in 2002. He co-founded the contract research organization Worldwide Clinical Trials and has held senior positions with Boot Pharmaceuticals, Bayer, Bristol-Myers Squibb and Merck.
